The overall aim of this proposal is to examine degeneration and regeneration of an adult brain structure, with the goal of better understanding the mature brain's ability to heal after damage. We have developed a model for synaptic plasticity in the olfactory bulb in zebrafish: one that produces temporary, partial deafferentation and allows potential regeneration of the adult brain to be observed. Repeated intranasal irrigation with Triton X-100 in this animal results in long-term, partial deafferentation of the olfactory bulb with a resulting deficit in bulb volume. Cessation of the detergent treatment allows the olfactory epithelium to recover and reinnervate the olfactory bulb, reversing the deafferentation-induced decrease in bulb volume. This proposal examines the mechanisms by which bulb volume is reduced and restored in this model. The hypothesis of this R15 proposal is that repeated chemical ablation of the olfactory epithelium produces deafferentation-related changes in cell genesis and cell survival in the olfactory bulb, and these effects are reversed with reinnervation by regenerated olfactory axons. Bromodeoxyuridine immunocytochemistry and TUNEL methods will be used to label newly formed cells and apoptotic cells, respectively. The first specific aim is to determine specific alterations in cell genesis and cell survival induced by repeated ablation of the olfactory epithelium with detergent. The hypothesis of this aim is that repeated assault on the olfactory epithelium by intranasal irrigation with detergent reduces the size of the olfactory bulb and this decrease in bulb size is possibly due to increased cell death and/or decreased cell genesis. Specific alterations in the patterns of cell genesis and cell survival will be analyzed to determine the effects of decreased afferent input on cell formation and cell fate. The second specific aim is to determine the effect of reinnervation on cell genesis and cell survival in the deafferented olfactory bulb. The hypothesis of this aim is that reinnervation will cause a reversal of the deafferentation-induced reduction in bulb size through decreased cell death and/or increased cell genesis. Zebrafish is used because it is an important model organism with similar basic cytoarchitecture as other vertebrates, including human, and the potential for future work on molecular mechanisms involved in brain plasticity. These studies permit investigation into the adult brain's potential for recovery from physical or functional deafferentation due to injury or disease. PUBLIC HEALTH RELEVANCE: This project examines the ability of the adult brain to recover from damage due to injury or disease. Cell genesis and cell death will be examined with a novel, reversible deafferentation method using repeated intranasal irrigation with detergent in zebrafish. This work will lead to a better understanding of the plasticity of the adult brain and the cellular interactions that are important in maintenance of adult brain structures.